Substituted benzamidine compounds which have useful pharmaceutical activity

ABSTRACT

Compounds of formula ##STR1## and their therapeutic use, inter alia, as LTB 4  -antagonists. Exemplary compounds are: 
     (Methoxycarbonyl-imino-{4&#39;- 2-(2-propylphenoxy)-ethoxy!-biphenyl-4-yl}-methyl)-amine; 
     (Benzyloxycarbonyl-imino-{4&#39;- 2-(2-propylphenoxy)-ethoxy!-biphenyl-4-yl}-methyl-amine; 
      Hydroxy-imino-(4-{3- 4-(1-methyl-1-phenylethyl)-phenoxymethyl!-benzoyloxy}phenyl)-methyl!-amine; 
      Ethoxycarbonyl-imino-(4-{3- 4-(1-methyl-1-phenylethyl)-phenoxymethyl!-benzoyloxy}phenyl)-methyl!-amine; and, 
      3&#39;-Pyridylcarbonyl-imino-(4-{3- 4-(1-methyl-1-phenylethyl)-phenoxymethyl!-benzyloxy}phenyl)-methyl!-amine.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application was field pursuant to 35 U.S.C. §371 and corresponds toInternational Application Number PCT/EP95/02112, filed on Jun. 3, 1995.

FIELD OF THE INVENTION

The invention relates to new substituted benzamidines, the preparationthereof using conventional methods and their use, as pharmaceuticalswith in particular, an LTB₄ -receptor-antagonist activity.

DESCRIPTION OF THE INVENTION

The new substituted benzamidines correspond to the formula ##STR2##wherein the A denotes the group ##STR3## X₁ denotes O, NH or NCH₃ X₂denotes O, NH, NCH₃ or ##STR4## X₃ denotes --X--C_(n) H_(2n) --; X₄denotes --C_(n) H_(2n) --X-- (n=1 or 2, X=O, NH or NCH₃);

R₁ denotes OH, CN, COR₁₂, COOR₁₂ or CHO;

R₂ denotes Br, Cl, F, CF₃, OH, C₁ -C₆ -alkyl, C₅ -C₇ -cycloalkyl, aryl,O-aryl, CH₂ -aryl, CR₅ R₆ -aryl, C(CH₃)₂ -R₇ ; and also H, when A is agroup of Formula III or when X₂ is a group of Formula IV; and also C₁-C₆ -alkoxy, when A is the group II, X₁ is as hereinbefore defined andX₂ denotes NH, NCH₃ or the group IV, or when A denotes the group III, X₃is as hereinbefore defined and in X₄ X denotes NH or NCH₃ ;

R₃ denotes H, C₁ -C₆ -alkyl, OH, Cl, F, and also C₁ -C₆ alkoxy when R₂denotes aryl, O-aryl, CH₂ -aryl, CR₅ R₆ -aryl or C(CH₃)₂ -R₇ or when X₂denotes the group IV;

R₂ and R₃ may also together denote a fused aromatic or heteroaromaticring;

R₄ denotes H or C₁ -C₆ -alkyl;

R₅ denotes C₁ -C₄ -alkyl, CF₃, CH₂ OH, COOH or COO (C₁ -C₄ -alkyl);

R₆ denotes H, C₁ -C₄ -alkyl, or CF₃ ;

R₅ and R₆ together may also form a C₄ -C₆ -alkylene group;

R₇ denotes CH₂ OH, COOH, COO(C₁ -C₄ -alkyl), CONR₁₀ R₁₁ or CH₂ NR₁₀ R₁₁;

R₈, R₉ denote H, Br, Cl, F, OH, C₁ -C₆ -alkyl or C₁ -C₆ -alkoxy;

R₁₀ denotes H, C₁ -C₆ -alkyl, phenyl, phenyl-(C₁ -C₆ -alkyl), COR₁₂,COOR₁₂, CHO, CONH₂, CONHR₁₂, SO₂ -(C₁ -C₆ -alkyl), SO₂ -phenyl, whereinthe phenyl group may be mono- or polysubstituted by Cl, F, CF₃, C₁ -C₄alkyl, OH, C₁ -C₄ -alkoxy;

R₁₁ denotes H or C₁ -C₆ -alkyl;

R₁₀ and R₁₁ together may also denote a C₄ -C₆ -alkylene group;

R₁₂ denotes C₁ -C₆ -alkyl, C₅ -C₇ -cycloalkyl, aryl, heteroaryl, aralkylor heteroaryl-(C₁ -C₆ -alkyl), wherein the aryl or heteroaryl group maybe mono or polysubstituted by Cl, F, CF₃, C₁ -C₄ -alkyl, OH or C₁ -C₄-alkoxy.

The new compounds may occur as free bases or as salts with acids,preferably physiological acceptable acids; if they contain one or morechiral centres, they may be in the form of racemates, inenantiomerically pure or concentrated form, optionally as pairs ofdiastereomers. Any tautomers (with --C(NH)--NHR₁) are also included.

The preferred compounds of Formula I are those wherein

A, m, n, X₃, X₄ and R₁ are as hereinbefore defined;

X₁ denotes O;

X₂ denotes O or a group IV (wherein X₁ equals O);

R₂ denotes Cl, F, CF₃, OH, C₁ -C₆ -alkyl, aryl, O-aryl, CH₂ -aryl or CR₅R₆ -aryl, and, if X₂ is the group IV, R₂ may also represent C₁ -C₆-alkoxy;

R₃ denotes H, C₁ -C₆ -alkyl or OH, and, if R₂ CR₅ R₆ -aryl, R₃ alsodenotes C₁ -C₆ -alkoxy;

R₄ denotes H;

R₅ denotes C₁ -C₃ -alkyl, CF₃ or CH₂ OH;

R₆ denotes H, C₁ -C₃ -alkyl or CF₃,

R₅ and R₆ together may also denote C₄ -C₅ -alkylene;

R₈ and R₉ denote H, F or OH.

Particular mention should be made of the compounds wherein, within thescope of the above definitions

X₁ denotes O;

X₂ represents the group IV (wherein X₁ equals O);

X denotes O;

R₁ denotes COOR₁₂ ;

R₂ denotes C₁ -C₆ -alkyl, aryl, O-aryl, CH₂ -aryl or CR₅ R₆ -aryl;

R₃ denotes H, OH or C₁ -C₆ -alkyl and, if R₂ is CR₅ R₆ -aryl, R₃ mayalso denote C₁ -C₆ alkoxy;

R₄ denotes H;

R₅ and R₆ denote C₁ -C₃ -alkyl or CF₃ ;

R₈ and R₉ denote H;

R₁₂ denotes C₁ -C₆ -alkyl, aralkyl or C₇ -C₅ -cycloalkyl.

Where the symbols according to the above definitions may have the sameor different meanings, both possibilities should be included. Aliphaticchains which have a sufficient number of carbon atoms may be straightchained or branched.

"Aryl" denotes an optionally (mono- or poly-) substituted aryl group,such as naphthyl, but preferably an optionally (mono- or poly-)substituted phenyl group. The preferred substituents are: Cl, F, Br, OH,C₁ -C₆ -alkyl, C₁ -C₆ -alkoxy, and CF₃ ; other possibilities are groupswhich are generally present only once, such as NH₂, NH(C₁ -C₆ -alkyl),N(C₁ -C₆ -alkyl)₂, NH(SO₂ -(C₁ -C₆ -alkyl, NH(SO₂ -phenyl), wherein thephenyl group may in turn be substituted, in particular by F, Cl, CF₃, C₁-C₄ -alkyl, C₁ -C₄ alkoxy or OH. The term "aralkyl" denotes a C₁ -C₆-alkyl group which is substituted by an aryl (as hereinbefore defined).The term "heteroaryl" here preferably refers to pyridyl, pyrimidyl,pyridazinyl and pyrazinyl, thienyl and furyl, which may be mono orpolysubstituted, in particular, by Cl, F, Br, OH, C₁ -C₆ -alkyl, C₁ -C₆-alkoxy, CF₃. The cycloalkyl groups may be substituted by C₁ -C₆ -alkylgroups, e.g. as in the menthyl group. If R₂ and R₃ together denote afused ring, this refers to a ring which forms a basis for aryl andheteroaryl groups as hereinbefore defined.

In the alkyl and alkoxy groups the number of carbon atoms is preferablybetween 1 and 4. The preferred substituents in aromatic orheteroaromatic groups are alkyl and alkoxy groups having up to 3,preferably up to 2, carbon atoms. The amidino group C(NH₂)NR₁ ispreferably in the the para-position relative to Group A.

The new compounds may be obtained by methods known per se, for exampleas follows:

1. Reacting an amidine as formula ##STR5## with a compound of formula

    L--R'.sub.1                                                (VI)

wherein in compound (V) A, R₂, R₃ and R₄ are as hereinbefore defined,R'₁ has the same meaning as R₁, with the exception of OH, and L denotesa nucleophilically exchangeable group such as a halogen atom (such asCl, Br) or acyloxy. The reaction is appropriately carried out in asolvent such as tetrahydrofuran, methylene chloride, chloroform ordimethylformamide, preferably in the presence of a base such as sodiumcarbonate, potassium carbonate or sodium hydroxide solution or in thepresence of a tertiary organic base such as triethylamine,N-ethyl-diisopropylamine, N-methyl-morpholine or pyridine which maysimultaneously serve as solvents, at temperatures between -30° and 100°C., but preferably at temperatures between -10° and 80° C.

2. Reacting compounds of Formula ##STR6## (wherein R₂, R₃, R₄ and X₁ areas hereinbefore defined), with a benzamidine derivative of Formula##STR7## (wherein L, m, n, X, X₂, X₄, R₁, R₈ and R₉ are as hereinbeforedefined).

3. Reacting compounds of Formula ##STR8## (wherein R₁ and X₂ are ashereinbefore defined) with a compound of Formula ##STR9## (wherein L, m,n, R₂, R₃, R₄, R₈, R₉, X₁ and X₃ are as hereinbefore defined). Methods 2and 3 are preferably carried out in aprotic solvents such asdimethylsulfoxde, dimethylformamide, acetonitrile or alcohols (e.g.methanol, ethanol, isopropanol) with the addition of basic substances(e.g. metal carbonates, metal hydroxides, metal hydrides) attemperatures between about 0° and 140° C. or at the boiling temperatureof the reaction mixture.

4. In order to prepare compounds of Formula I wherein R₁ denotes OH; anitrile of formula ##STR10## wherein A, R₂, R₃ and R₄ are ashereinbefore defined, as reacted with hydroxylamine. Method 4 ispreferably carried out in an alcohol (methanol, ethanol, propanol) or anaprotic solvent such as dimethylsulfoxide, dimethylformamide, oracetonitrile, or optionally in admixture with water, in warm conditions.The hydroxylamine is used, for example, in the form of the hydrochlorideor methane sulfonate, and a suitable base such as sodium carbonate isadded.

The starting materials may be synthesised using conventional methods.

It has been found that the compounds of Formula 1 are characterised bytheir versatility in the therapeutic field. Particular mention should bemade of those possible applications for which the LTB₄-receptor-antagonistic properties come into play. Example include, inparticular: arthritis, asthma, chronic obstructive lung diseases, suchas chronic bronchitis, psoriasis, ulcerative colitis, gastro orenteropathy induced by non-steroidal antiphlogistics, Alzheimersdisease, shock, reperfusion damage/ischaemia, atherosclerosis andmultiple sclerosis.

The new compounds may also be used to treat diseases or conditions inwhich the passage of cells from the blood through the vascularendothelium into tissue is of importance (such as metastasis) ordiseases and conditions in which the combination of LTB₄ or anothermolecule (for example 12-HETE) with the LTB₄ -receptor influences cellproliferation (such as chronic myelocytic leukaemia).

The new compounds may also be used in conjunction with other activesubstances, e.g. those which are used for the same indications or, forexample, with antiallergics, secretolytics, β₂ -adrenergics, steroidsadministered by inhalation, antihistamines and/or PAF-antagonists. Thesubstances may be administered topically, orally, transdermally,nasally, parenterally or by inhalation.

The new compounds are characterised by being well tolerated and havinggood bioavailability.

The therapeutic or prophylactic dose depends not only on the potency onthe individual compounds and the body weight of the patient, but also onthe nature and gravity of the condition. For oral use the dose isbetween 10 and 500 mg, preferably between 20 and 250 mg. For inhalationa dosage of between 0.5 and 25, preferably between 2 and 20 mg of activesubstance is delivered to the patient. Inhalation solutions generallycontain between about 0.5 and 5% of active substance. The new compoundsmay be administered, e.g. as plain or coated tablets, capsules,lozenges, powders, granules, solutions, emulsions, syrups, inhalationaerosols, ointments or suppositories.

Pharmacological and biochemical investigation of the activity may becarried out using tests as described for example in WO 16036, Pages 15to 17.

EXAMPLES OF FORMULATIONS

1. Tablets

Composition:

    ______________________________________                                        Active substance according                                                                         20 parts by weight                                       to the invention                                                              Stearic acid         6 parts by weight                                        Glucose              474 parts by weight                                      ______________________________________                                    

The ingredients are processed in the usual way to form tablets weighing500 mg. If desired, the content of active substance increased or reducedand the quantity of glucose increased or reduced accordingly.

2. Suppositories

Compositions:

    ______________________________________                                        Active substance according                                                                        100 parts by weight                                       to the invention                                                              Powdered lactose    45 parts by weight                                        Cocoa butter        1555 parts by weight                                      ______________________________________                                    

The ingredients are processed in the usual way to form suppositoriesweighing 1.7 g.

3. Inhalation powder

Micronised powdered active substance (Compound of formula 1; particlesize of about 0.5 to 7 μm) is packed into hard gelatine capsules in aquantity of 5 mg, optionally with the addition of micronised lactose.The powder is inhaled from conventional inhalers, e.g. according to DE-A33 45 722.

The following Examples provide a guide to the preparation of the newcompounds.

Example 1

(Methoxycarbonyl-imino-(4'-2-(2-propylphenoxy)-ethoxy)-biphenyl-4-yl)-methyl)-amine ##STR11##

3.8 g of the amidine compound of the above formula (R equals NH), whichmay be obtained by conventional methods, e.g. using the method accordingto WO 93/16036, are suspended in 200 ml of chloroform. 1.6 ml oftriethylamine are added and 0.8 ml of methyl chloroformate are addeddropwise at ambient temperature. After the components have dissolved themixture is stirred for 3 hours, then extracted three times with water,evaporated down and the residue is stirred with ether and suctionfiltered. Yield of compound of the above formula wherein R equalsNCOOCH₃ : 3.7 g, melting point 170°-176° C.

Example 2

(Benzyloxycarbonyl-imino-{4'-2-(2-propylphenoxy)-ethoxy-biphenyl-4-yl}methyl)-amine ##STR12##

2.6 g of the amidine compound of the above formula (R=NH) are placed in200 ml of chloroform. 1.3 ml of triethylamine are added and 1 ml ofbenzylchloroformate is added dropwise at ambient temperature. After thecomponents have dissolved, the mixture is stirred for 3 hours, thenextracted three times with water, evaporated down and the residue isstirred with ether and suction filtered. The substance is recrystallisedfrom ethanol. Yield of the compound of the above formula whereinR=NCOOCH₂ Ph: 2.2 g, Mp. 128°-131° C. Compounds with other groups Rprepared in an analogous way:

R=NCOOC₂ H₅ ; Mp. 120°-123° C.

R=NCOO-n-C₃ H₇ ; Mp. 113°-114° C.

R=NCOO-i-C₃ H₇ ; Mp. 110°-117° C.

R=NCOO-n-C₄ H₉ ; Mp. 135°-138° C.

R=NCOO-i-C₄ H₉ ; Mp. 103° C.

R=NCOO-t-C₄ H₉ ; Mp. 129°-132° C.

R=NCOO-n-C₆ H₁₃ ; Mp. 117°-121° C.

Example 3

3.5 g of the amidine compound of the above formula (R=NH) are placed in150 ml of chloroform. 2 ml of triethylamine are added and 1 ml ofdi-tert.-butyldicarbonate is added dropwise at ambient temperature.After the components have dissolved, the mixture is stirred for 3 hours,then extracted three times with water, evaporated down and the residueis stirred with ether and suction filtered. The substance isrecrystallised from 20 ml of ethanol. Yield of the compound of the aboveformula wherein R=N-COO-t-butyl: 3 g, Mp. 129°-132° C.

Example 4

(a) Hydroxy-imino-(4-{3-4-(1-methyl-1-phenylethyl)-phenoxymethyl!benzyloxy}phenyl)-methyl!-amine##STR13##

5.25 g of nitrile of the above formula (R=CN, prepared by conventionalmethods) are placed in 60 ml of ethanol and heated to boiling. In thecourse of 30 minutes, a solution of 2.7 g of sodium carbonate and 3.4 gof hydroxylamine hydrochloride in 10 ml of water is added dropwise. Themixture is then refluxed for 5 hours. After cooling, the mixture isevaporated down, the residue is taken up in 50 ml of water and extractedthree times with 40 ml of ethyl acetate. The organic phases are driedover MgSO₄, filtered and concentrated by evaporation. The crystals aretaken up in 20 ml of acetone and acidified with ethereal hydrochloricacid. After brief dissolution, 5.3 g of the hydrochloride of theamidoxime of the above formula are obtained wherein R=C(NOH)--NH₂. Mp.180°-181° C.

(b) Imino-(4-{3-4-(1-methyl-1-phenylethyl)-phenoxymethyl!-benzyloxy}phenyl)-methyl!-amine##STR14##

5.1 g of the amidoxime of the above formula (R=NOH) are dissolved in 120ml of methanol and hydrogenated in the presence of 10 g ofmethanol-moistened Raney nickel for 2 hours under normal pressure and atambient temperature. The nickel is removed by suction filtration and thesolution is filtered over silica gel. The filtrate is acidified withethanolic hydrochloric acid, the solution is evaporated down andrecrystallised from ethanol. The yield is 3.3 g of the amidine compound(in the above formula, R=NH). Mp. 160° C.

(c) Ethoxycarbonyl-imino-(4-{3-4-(1-methyl-1-phenylethyl)-phenoxymethyl!benzyloxy}phenyl)-methyl!-amine

2.44 g of the amidine compound of the above formula (R=NH) obtainedaccording to (b) are placed in 150 ml of dichloromethane, 0.6 g ofethylchloroformate are added, then at ambient temperature 52.5 ml of0.2N sodium hydroxide solution are added dropwise over 15 minutes. Thesolution obtained is stirred for 2 hours at ambient temperature, thenthe organic phase is separated, extracted with 100 ml of water and driedover sodium sulphate. The solution is evaporated down and the residue isrecrystallised from 10 ml of ethanol. 2.1 g of title compound areobtained (R=NCOOC₂ H₅), Mp. 99° C.

The following compounds of the formula given in Example 4(b), forexample, may be obtained analogously:

R=NCOO-(-)-menthyl; Mp. 113° C.

R=NCO--C₆ H₅ ; Mp. 101°-103° C.

Example 5

3'-Pyridylcarbonyl-imino-(4-{3-4-(1-methyl-1-phenylethyl)-phenoxymethyl!-benzyloxy}phenyl)-methyl!-amine

5.0 g of the amidine compound of the above formula (R=NH, cf. Example4(b)) are placed in 250 ml of dichloromethane. Over 10 minutes, atambient temperature, a solution of 3.9 g of nicotinic acid chloridehydrochloride and 16.3 ml of triethylamine in 50 ml of dichloromethaneis added dropwise. After 15 hours at ambient temperature the mixture isextracted twice with 300 ml of water, the organic phase is dried oversodium sulphate, filtered and the filtrate is evaporated down. Theresidue is purified by low-pressure chromatography over silica gel 60using ethyl acetate, the product is dissolved in 50 ml of acetone,acidified with ethanolic hydrochloric acid and precipitated with etheras its hydrochloride. The yield is 2.0 g of the nicotinoyl derivative ofthe above formula wherein R=N--CO-3-pyridyl, Mp. 172° C.

The following compounds may also be prepared, inter alia, analogouslywith the Examples: ##STR15##

We claim:
 1. A compound of the formulawherein A denotes the group##STR16## X₁ denotes O, NH or NCH₃ X₂ denotes O, NH, NCH₃ or ##STR17##X₃ denotes --X--C_(n) H_(2n) --; X₄ denotes --C_(n) H_(2n) --X--; ndenotes 1 or 2; X denotes O, NH or NCH₃ ; R₁ denotes OH, CN, COR₁₂,COOR₁₂ or CHO; R₂ denotes H (provided that A is a group of Formula IIIor X₂ is a group of Formula IV), Br, Cl, F, CF₃, OH, C₁ -C₆ -alkyl, C₅-C₇ -cycloalkyl, C₁ -C₆ -alkoxy (provided that A is the group II, X₁ isas hereinbefore defined and X₂ denotes NH, NCH₃ or the group IV, orprovided that A denotes the group III, X₃ is as hereinbefore definedand, in X₄, X denotes NH or NCH₃), aryl, O-acryl, CH₂ -aryl, CR₅ R₆-aryl, or C(CH₃)₂ -R₇ ; R₃ denotes H, C₁ -C₆ -alkyl, OH, Cl, F, and alsoC₁ -C₆ alkoxy when R₂ denotes aryl, O-aryl, CH₂ -aryl, CR₅ R₆ -aryl orC(CH₃)₂ -R₇ or when X₂ denotes the group IV; R₂ and R₃, in thealternative, may also together denote a fused aromatic or heteroaromaticring; R₄ denotes H or C₁ -C₆ -alkyl; R₅ denotes C₁ -C₄ -alkyl, CF₃, CH₂OH, COOH or COO(C₁ -C₄ -alkyl); R₆ denotes H, C₁ -C₄ -alkyl, or CF₃ ; R₅and R₆, in the alternative, may also together form a C₄ -C₆ -alkylenegroup; R₇ denotes CH₂ OH, COOH, COO(C₁ -C₄ -alkyl), CONR₁₀ R₁₁ or CH₂NR₁₀ R₁₁ ; R₈ and R₉ each independently denote H, Br, Cl, F, OH, C₁ -C₆-alkyl or C₁ -C₆ -alkoxy; R₁₀ denotes H, C₁ -C₆ -alkyl, phenyl,phenyl-(C₁ -C₆ -alkyl), COR₁₂, COOR₁₂, CHO, CONH₂, CONHR₁₂, SO₂ -(C₁ -C₆-alkyl), SO₂ -phenyl, wherein each of the phenyl groups may be mono- orpolysubstituted by groups selected from Cl, F, CF₃, C₁ -C₄ -alkyl, OHand C₁ -C₄ -alkoxy; R₁₁ denotes H or C₁ -C₆ -alkyl; R₁₀ and R₁₁, in thealternative, may also together denote a C₄ -C₆ -alkylene group; and, R₁₂denotes C₁ -C₆ -alkyl, C₅ -C₇ -cycloalkyl, aryl, heteroaryl, aralkyl orheteroaryl-(C₁ -C₆ -alkyl), wherein the aryl or heteroaryl group may bemono or polysubstituted by Cl, F, CF₃, C₁ -C₄ -alkyl, OH or C₁ -C₄-alkoxy;wherein each of the above-mentioned aryl groups denotes phenyland each of the above-mentioned heteroaryl groups denotes pyridyl,pyrimidyl, pyridazinyl, pyrazinyl, thienyl or furyl, and wherein eachsuch aryl or heteroaryl group is, unless otherwise specified, eitherunsubstituted or mono- or poly-substituted with a group selected fromCl, F, Br, OH, C₁ -C₆ -alkyl, C₁ -C₆ -alkoxy and CF₃ ; or a tautomer orpharmaceutically acceptable salt thereof;with the proviso that if Adenotes a group --X₁ --C_(m) H_(2m) --X₂ --wherein m represents aninteger 2, 3, or 4; X₁ denotes O, NH; X₂ denotes O, NH or ##STR18## R₂denotes hydrogen, Br, Cl, CF₃, C₁ -C₆ -alkyl, phenyl; R₃ denoteshydrogen, C₁ -C₆ -alkyl, hydroxy, Cl, F, C₁ -C₆ -alkoxy; and, R₄ denoteshydrogen, C₁ -C₆ -alkyl; then, R₁ must not denote hydroxy.
 2. A compoundof the formula I, in accordance with claim 1, wherein,X₁ denotes O; X₂denotes O or a group IV (wherein X₁ equals O); R₂ denotes Cl, F, CF₃,OH, C₁ -C₆ -alkyl, aryl, O-aryl, CH₂ -aryl or CR₅ R₆ -aryl, and, if X₂is the group IV, R₂ may also represent C₁ -C₆ -alkoxy; R₃ denotes H, C₁-C₆ -alkyl or OH, and, if R₂ is CR₅ R₆ -aryl, R₃ may also denote C₁ -C₆-alkoxy; R₄ denotes H; R₅ denotes C₁ -C₃ -alkyl, CF₃ or CH₂ OH; R₆denotes H, C₁ -C₃ -alkyl or CF₃, R₅ and R₆ together may also denote C₄-C₅ -alkylene; and, R₈ and R₉ each independently denote H, F or OH.
 3. Acompound of the formula I, in accordance with claim 1, whereinX₁ denotesO; X₂ denotes the group IV (wherein X₁ equals O); X denotes O; R₁denotes COOR₁₂ ; R₂ denotes C₁ -C₆ -alkyl, aryl, O-aryl, CH₂ -aryl orCR₅ R₆ -aryl; R₃ denotes H, OH or C₁ -C₆ -alkyl and, if R₂ is CR₅ R₆-aryl, R₃ may also denote C₁ -C₆ alkoxy; R₄ denotes H; R₅ and R₆ eachindependently denote C₁ -C₃ -alkyl or CF₃ ; R₈ and R₉ each denote H;and, R₁₂ denotes C₁ -C₆ -alkyl, aralkyl or C₇ -C₅ -cycloalkyl. 4.(Methoxycarbonyl-imino-{4'-2-(2-propylphenoxy)-ethoxy!-biphenyl-4-yl}-methyl)-amine or apharmaceutically acceptable salt thereof. 5.(Benzyloxycarbonyl-imino-{4'-2-(2-propylphenoxy)-ethoxy!-biphenyl-4-yl}-methyl)-amine or apharmaceutically acceptable salt thereof.
 6. Hydroxy-imino-(4-{3-4-(1-methyl-1-phenylethyl)-phenoxymethyl!-benzoyloxy}phenyl)-methyl!-amineor a pharmaceutically acceptable salt thereof. 7.Ethoxycarbonyl-imino-(4-{3-4-(1-methyl-1-phenylethyl)-phenoxymethyl!-benzoyloxy}phenyl)-methyl!-amineor a pharmaceutically acceptable salt thereof. 8.3'-Pyridylcarbonyl-imino-(4-{3-4-(1-methyl-1-phenylethyl)-phenoxymethyl!-benzyloxy}phenyl)-methyl!-amineor a pharmaceutically acceptable salt thereof.
 9. A pharmaceuticalcomposition comprising a compound of the formula I, in accordance withclaim 1, and a pharmacologically acceptable diluent, excipient orcarrier.
 10. A method for treating an inflammatory disease whichcomprises administering a compound of the formula ##STR19## wherein Adenotes the group ##STR20## X₁ denotes O, NH or NCH₃ X₂ denotes O, NH,NCH₃ or ##STR21## X₃ denotes --X--C_(n) H_(2n) --; X₄ denotes --C_(n)H_(2n) --X--;n denotes 1 or 2; X denotes O, NH or NCH₃ ; R₁ denotes OH,CN, COR₁₂, COOR₁₂ or CHO; R₂ denotes H (provided that A is a group ofFormula III or X₂ is a group of Formula IV), Br, Cl, F, CF₃, OH, C₁ -C₆-alkyl, C₅ -C₇ -cycloalkyl, C₁ -C₆ -alkoxy (provided that A is the groupII, X₁ is as hereinbefore defined and X₂ denotes NH, NCH₃ or the groupIV, or provided that A denotes the group III, X₃ is as hereinbeforedefined and, in X₄, X denotes NH or NCH₃), aryl, O-aryl, CH₂ -aryl, CR₅R₆ -aryl, or C(CH₃)%₂ -R₇ ; R₃ denotes H, C₁ -C₆ -alkyl, OH, Cl, F, andalso C₁ -C₆ alkoxy when R₂ denotes aryl, O-aryl, CH₂ -aryl, CR₅ R₆ -arylor C(CH₃)₂ -R₇ or when X₂ denotes the group IV; R₂ and R₃, in thealternative, may also together denote a fused aromatic or heteroaromaticring; R₄ denotes H or C₁ -C₆ -alkyl; R₅ denotes C₁ -C₄ -alkyl, CF₃, CH₂OH, COOH or COO(C₁ -C₄ -alkyl); R₆ denotes H, C₁ -C₄ -alkyl, or CF₃ ; R₅and R₆, in the alternative, may also together form a C₄ -C₆ -alkylenegroup; R₇ denotes CH₂ OH, COOH, COO(C₁ -C₄ -alkyl), CONR₁₀ R₁₁ or CH₂NR₁₀ R₁₁ ; R₈ and R₉ each independently denote H, Br, Cl, F, OH, C₁ -C₆-alkyl or C₁ -C₆ -alkoxy; R₁₀ denotes H, C₁ -C₆ -alkyl, phenyl,phenyl-(C₁ -C₆ -alkyl), COR₁₂, COOR₁₂, CHO, CONH₂, CONHR₁₂, SO₂ -(C₁ -C₆-alkyl), SO₂ -phenyl, wherein each of the phenyl groups may be mono- orpolysubstituted by groups selected from Cl, F, CF₃, C₁ -C₄ -alkyl, OHand C₁ -C₄ -alkoxy; R₁₁ denotes H or C₁ -C₆ -alkyl; R₁₀ and R₁₁, in thealternative, may also together denote a C₄ -C₆ -alkylene group; and, R₁₂denotes C₁ -C₆ -alkyl, C₅ -C₇ -cycloalkyl, aryl, heteroaryl, aralkyl orheteroaryl-(C₁ -C₆ -alkyl), wherein the aryl or heteroaryl group may bemono or polysubstituted by Cl, F, CF₃, C₁ -C₄ -alkyl, OH or C₁ -C₄-alkoxy;wherein each of the above-mentioned aryl groups denotes phenyland each of the above-mentioned heteroaryl groups denotes pyridyl,pyrimidyl, pyridazinyl pyrazinyl, thienyl or furyl, and wherein eachsuch aryl or heteroaryl group is, unless otherwise specified, eitherunsubstituted or mono- or poly-substituted with a group selected fromCl, F, Br, OH, C₁ -C₆ -alkyl, C₁ -C₆ -alkoxy and CF₃ ; or a tautomer orpharmaceutically acceptable salt thereof.
 11. A method for treating anallergic process which comprises administering a therapeutic amount of acompound of the formula ##STR22## wherein A denotes the group ##STR23##X₁ denotes O, NH or NCH₃ X₂ denotes O, NH, NCH₃ or ##STR24## X₃ denotes--X--C_(n) H_(2n) --; X₄ denotes --C_(n) H_(2n) --X--;n denotes 1 or 2;X denotes O, NH or NCH₃ ; R₁ denotes OH, CN, COR₁₂, COOR₁₂ or CHO; R₂denotes H (provided that A is a group of Formula III or X₂ is a group ofFormula IV), Br, Cl, F, CF₃, OH, C₁ -C₆ alkyl, C₅ -C₇ cycloalkyl, C₁ -C₆: alkoxy (provided that A is the group II, X₁ is as hereinbefore definedand X₂ denotes NH, NCH₃ or the group IV, or provided that A denotes thegroup III, X₃ is as hereinbefore defined and, in X₄, X denotes NH orNCH₃), aryl, O-aryl, CH₂ -aryl, CR₅ R₆ -aryl, or C(CH₃)₂ -R₇ ; R₃denotes H, C₁ -C₆ -alkyl, OH, Cl, F, and also C₁ -C₆ alkoxy when R₂denotes aryl, O-aryl, CH₂ -aryl, CR₅ R₆ -aryl or C(CH₃)₂ -R₇ or when X₂denotes the group IV; R₂ and R₃, in the alternative, may also togetherdenote a fused aromatic or heteroaromatic ring; R₄ denotes H or C₁ -C₆-alkyl; R₅ denotes C₁ -C₄ -alkyl, CF₃, CH₂ OH, COOH or COO(C₁ -C₄-alkyl); R₆ denotes H, C₁ -C₄ -alkyl, or CF₃ ; R₅ and R₆, in thealternative, may also together form a C₄ -C₆ -alkylene group; R₇ denotesCH₂ OH, COOH, COO(C₁ -C₄ -alkyl), CONR₁₀ R₁₁ or CH₂ NR₁₀ R₁₁ ; R₈ and R₉each independently denote H, Br, Cl, F, OH, C₁ -C₆ -alkyl or C₁ -C₆-alkoxy; R₁₀ denotes H, C₁ -C₆ -alkyl, phenyl, phenyl-(C₁ -C₆ -alkyl),COR₁₂, COOR₁₂, CHO, CONH₂, CONHR₁₂, SO₂ -(C₁ -C₆ -alkyl), SO₂ -phenyl,wherein each of the phenyl groups may be mono- or polysubstituted bygroups selected from Cl, F, CF₃, C₁ -C₄ -alkyl, OH and C₁ -C₄ -alkoxy;R₁₁ denotes H or C₁ -C₆ -alkyl; R₁₀ and R₁₁, in the alternative, mayalso together denote a C₄ -C₆ -alkylene group; and, R₁₂ denotes C₁ -C₆-alkyl, C₅ -C₇ -cycloalkyl, aryl, heteroaryl, aralkyl or heteroaryl-(C₁-C₆ -alkyl), wherein the aryl or heteroaryl group may be mono orpolysubstituted by Cl, F, CF₃, C₁ -C₄ -alkyl, OH or C₁ -C₄-alkoxy;wherein each of the above-mentioned aryl groups denotes phenyland each of the above-mentioned heteroaryl groups denotes pyridyl,pyrimidyl, pyridazinyl, pyrazinyl, thienyl or furyl, and wherein eachsuch aryl or heteroaryl group is, unless otherwise specified, eitherunsubstituted or mono- or poly-substituted with a group selected fromCl, F, Br, OH, C₁ -C₆ -alkyl, C₁ -C₆ -alkoxy and CF₃ ; or a tautomer orpharmaceutically acceptable salt thereof.
 12. A method for treating acondition selected from the group consisting of arthritis, asthma,chronic obstructive lung diseases, psoriasis, ulcerative colitis,Alzheimer's disease, shock, atherosclerosis, and multiple sclerosis,which comprises administering a compound of the formula ##STR25##wherein A denotes the group ##STR26## X₁ denotes O, NH or NCH₃ X₂denotes O, NH, NCH₃ or ##STR27## X₃ denotes --X--C_(n) H_(2n) --; X₄denotes --C_(n) H_(2n) --X--;n denotes 1 or 2; X denotes O, NH or NCH₃ :R₁ denotes OH, CN, COR₁₂, COOR₁₂ or CHO; R₂ denotes H (provided that Ais a group of Formula III or X₂ is a group of Formula IV), Br, Cl, F,CF₃, OH, C₁ -C₆ -alkyl, C₅ -C₇ -cycloalkyl, C₁ -C₆ -alkoxy (providedthat A is the group II, X₁ is as hereinbefore defined and X₂ denotes NH,NCH₃ or the group IV, or provided that A denotes the group III, X₃ is ashereinbefore defined and, in X₄, X denotes NH or NCH₃), aryl, O-aryl,CH₂ -aryl, CR₅ R₆ -aryl, or C(CH₃)₂ -R₇ ; R₃ denotes H, C₁ -C₆ -alkyl,OH, Cl, F, and also C₁ -C₆ alkoxy when R₂ denotes aryl, O-aryl, CH₂-aryl, CR₅ R₆ -aryl or C(CH₃)₂ -R₇ or when X₂ denotes the group IV; R₂and R₃, in the alternative, may also together denote a fused aromatic orheteroaromatic ring; R₄ denotes H or C₁ -C₆ -alkyl; R₅ denotes C₁ -C₄-alkyl, CF₃, CH₂ OH, COOH or COO(C₁ -C₄ -alkyl); R₆ denotes H, C₁ -C₄-alkyl, or CF₃ ; R₅ and R₆, in the alternative, may also together form aC₄ -C₆ -alkylene group; R₇ denotes CH₂ OH, COOH, COO(C₁ -C₄ -alkyl),CONR₁₀ R₁₁ or CH₂ NR₁₀ R₁₁ ; R₈ and R₉ each independently denote H, Br,Cl, F, OH, C₁ -C₆ -alkyl or C₁ -C₆ -alkoxy; R₁₀ denotes H, C₁ -C₆-alkyl, phenyl, phenyl-(C₁ -C₆ -alkyl), COR₁₂, COOR₁₂, CHO, CONH₂,CONHR₁₂, SO₂ -(C₁ -C₆ -alkyl), SO₂ -phenyl, wherein each of the phenylgroups may be mono- or polysubstituted by groups selected from Cl, F,CF₃, C₁ -C₄ -alkyl, OH and C₁ -C₄ -alkoxy; R₁₁ denotes H or C₁ -C₆-alkyl; R₁₀ and R₁₁, in the alternative, may also together denote a C₄-C₆ -alkylene group; and, R₁₂ denotes C₁ -C₆ -alkyl, C₅ -C₇ -cycloalkyl,aryl, heteroaryl, aralkyl or heteroaryl-(C₁ -C₆ -alkyl), wherein thearyl or heteroaryl group may be mono or polysubstituted by Cl, F, CF₃,C₁ -C₄ -alkyl, OH or C₁ -C₄ -alkoxy;wherein each of the above-mentionedawl groups denotes phenyl and each of the above-mentioned heteroarylgroups denotes pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thienyl orfuryl, and wherein each such awl or heteroaryl group is, unlessotherwise specified, either unsubstituted or mono- or poly-substitutedwith a group selected from Cl, F, Br, OH, C₁ -C₆ -alkyl, C₁ -C₆ -alkoxyand CF₃ ; or a tautomer or pharmaceutically acceptable salt thereof. 13.A method for treating of gastropathy induced by a non-steroidalanti-inflammatory agent which comprises administering a therapeuticamount of a compound of the formula ##STR28## wherein A denotes thegroup ##STR29## X₁ denotes O, NH or NCH₃ X₂ denotes O, NH, NCH₃ or##STR30## X₃ denotes --X--C_(n) H_(2n) --; X₄ denotes --C_(n) H_(2n)--X--;n denotes 1 or 2; X denotes O, NH or NCH₃ : R₁ denotes OH, CN,COR₁₂, COOR₁₂ or CHO; R₂ denotes H (provided that A is a group ofFormula III or X₂ is a group of Formula IV), Br, Cl, F, CF₃, OH, C₁ -C₆-alkyl, C₅ -C₇ -cycloalkyl, C₁ -C₆ -alkoxy (provided that A is the groupII, X₁ is as hereinbefore defined and X₂ denotes NH, NCH₃ or the groupIV, or provided that A denotes the group III, X₃ is as hereinbeforedefined and, in X₄, X denotes NH or NCH₃), aryl, O-aryl, CH₂ -aryl, CR₅R₆ -aryl, or C(CH₃)₂ -R₇ ; R₃ denotes H, C₁ -C₆ -alkyl, OH, Cl, F, andalso C₁ -C₆ alkoxy when R₂ denotes aryl, O-aryl, CH₂ -aryl, CR₅ R₆ -arylor C(CH₃)₂ -R₇ or when X₂ denotes the group IV; R₂ and R₃, in thealternative, may also together denote a fused aromatic or heteroaromaticring; R₄ denotes H or C₁ -C₆ -alkyl; R₅ denotes C₁ -C₄ -alkyl, CF₃, CH₂OH, COOH or COO(C₁ -C₄ -alkyl); R₆ denotes H, C₁ -C₄ -alkyl, or CF₃ ; R₅and R₆, in the alternative, may also together form a C₄ -C₆ -alkylenegroup; R₇ denotes CH₂ OH, COOH, COO(C₁ -C₄ -alkyl), CONR₁₀ R₁₁ or CH₂NR₁₀ R₁₁ ; R₈ and R₉ each independently denote H, Br, Cl, F, OH, C₁ -C₆-alkyl or C₁ -C₆ -alkoxy; R₁₀ denotes H, C₁ -C₆ -alkyl, phenyl,phenyl-(C₁ -C₆ -alkyl), COR₁₂, COOR₁₂, CHO, CONH₂, CONHR₁₂, SO₂ -(C₁ -C₆-alkyl), SO₂ -phenyl, wherein each of the phenyl groups may be mono- orpolysubstituted by groups selected from Cl, F, CF₃, C₁ -C₄ -alkyl, OHand C₁ -C₄ -alkoxy; R₁₁ denotes H or C₁ -C₆ -alkyl; R₁₀ and R₁₁, in thealternative, may also together denote a C₄ -C₆ -alkylene group; and, R₁₂denotes C₁ -C₆ -alkyl, C₅ -C₇ -cycloalkyl, aryl, heteroaryl, aralkyl orheteroaryl-(C₁ -C₆ -alkyl), wherein the aryl or heteroaryl group may bemono or polysubstituted by Cl, F, CF₃, C₁ -C₄ -alkyl, OH or C₁ -C₄-alkoxy;wherein each of the above-mentioned aryl groups denotes phenyland each of the above-mentioned heteroaryl groups denotes pyridyl,pyrimidyl, pyridazinyl, pyrazinyl, thienyl or furyl, and wherein eachsuch aryl or heteroaryl group is, unless otherwise specified, eitherunsubstituted or mono- or poly-substituted with a group selected fromCl, F, Br, OH, C₁ -C₆ -alkyl, C₁ -C₆ -alkoxy and CF₃ ; or a tautomer orpharmaceutically acceptable salt thereof.
 14. A method for treatingmetastasis and chronic myelocytic leukaemia which comprisesadministering a therapeutic amount of a compound of the formula##STR31## wherein A denotes the group ##STR32## X₁ denotes O, NH or NCH₃X₂ denotes O, NH, NCH₃ or ##STR33## X₃ denotes --X--C_(n) H_(2n) --; X₄denotes --C_(n) H_(2n) --X--;n denotes 1 or 2; X denotes O, NH or NCH₃ ;R₁ denotes OH, CN, COR₁₂, COOR₁₂ or CHO; R₂ denotes H (provided that Ais a group of Formula III or X₂ is a group of Formula IV), Br, Cl, F,CF₃, OH, C₁ -C₆ -alkyl, C₅ -C₇ -cycloalkyl, C₁ -C₆ -alkoxy (providedthat A is the group II, X₁ is as hereinbefore defined and X₂ denotes NH,NCH₃ or the group IV, or provided that A denotes the group III, X₃ is ashereinbefore defined and, in X₄, X denotes NH or NCH₃), aryl, O-aryl,CH₂ -aryl, CR₅ R₆ -aryl, or C(CH₃)₂ -R₇ ; R₃ denotes H, C₁ -C₆ -alkyl,OH, Cl, F, and also C₁ -C₆ alkoxy when R₂ denotes aryl, O-aryl, CH₂-aryl, CR₅ R₆ -aryl or C(CH₃)₂ -R₇ or when X₂ denotes the group IV; R₂and R₃, in the alternative, may also together denote a fused aromatic orheteroaromatic ring; R₄ denotes H or C₁ -C₆ -alkyl; R₅ denotes C₁ -C₄-alkyl, CF₃, CH₂ OH, COOH or COO(C₁ -C₄ -alkyl); R₆ denotes H, C₁ -C₄-alkyl, or CF₃ ; R₅ and R₆, in the alternative, may also together form aC₄ -C₆ -alkylene group; R₇ denotes CH₂ OH, COOH, COO(C₁ -C₄ -alkyl),CONR₁₀ R₁₁ or CH₂ NR₁₀ R₁₁ ; R₈ and R₉ each independently denote H, Br,Cl, F, OH, C₁ -C₆ -alkyl or C₁ -C₆ -alkoxy; R₁₀ denotes H, C₁ -C₆-alkyl, phenyl, phenyl-(C₁ -C₆ -alkyl), COR₁₂, COOR₁₂, CHO, CONH₂,CONHR₁₂, SO₂ -(C₁ -C₆ -alkyl), SO₂ -phenyl, wherein each of the phenylgroups may be mono- or polysubstituted by groups selected from Cl, F,CF₃, C₁ -C₄ -alkyl, OH and C₁ -C₄ -alkoxy; R₁₁ denotes H or C₁ -C₆-alkyl; R₁₀ and R₁₁, in the alternative, may also together denote a C₄-C₆ -alkylene group; and, R₁₂ denotes C₁ -C₆ -alkyl, C₅ -C₇ -cycloalkyl,aryl, heteroaryl, aralkyl or heteroaryl-(C₁ -C₆ -alkyl), wherein thearyl or heteroaryl group may be mono or polysubstituted by Cl, F, CF₃,C₁ -C₄ -alkyl, OH or C₁ -C₄ -alkoxy;wherein each of the above-mentionedaryl groups denotes phenyl and each of the above-mentioned heteroarylgroups denotes pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thienyl orfuryl, and wherein each such aryl or heteroaryl group is, unlessotherwise specified, either unsubstituted or mono- or poly-substitutedwith a group selected from Cl, F, Br, OH, C₁ -C₆ C-alkyl, C₁ -C₆ -alkoxyand CF₃ ; or a tautomer or pharmaceutically acceptable salt thereof.